1. Field of the Invention
The present invention relates to .alpha.-arylcarbamoyl cyanoacetic acid derivatives active as anti-inflammatory and anti-arthritic agents, to their use in the treatment of inflammatory or arthritic conditions, and to pharmaceutical compositions containing the novel compounds. More particularly, the invention relates to the esters, thioesters, and amides of .alpha.-arylcarbamoyl cyanoacetic acid.
2. Description of Related Art
Benzoylacetonitrile (I) and its monofluoro analogues have been found to be effective inhibitors of adjuvant-induced arthritis in rats (J. Med. Chem., 1979, 22:1385-9). The same article, as well as U.S. Pat. No. 4,189,436, also discloses .beta.-oxo-.beta.-thiophenepropionitriles (II) as anti-arthritic agents. ##STR1##
.beta.-Oxopropionitriles having an .alpha.-carbonyl or thiocarbonyl substituent are reported as anti-inflammatory and/or anti-arthritic agents in (a) through (e):
(a) U.S. Pat. No. 4,061,767 and German Offenlegungsschrift No. 2,555,789 disclose, respectively, 2-hydroxyethylidenecyanoacetic acid anilide derivatives of formulas (IIIa) and
(IIIb), wherein Ar is inter alia mono-, di-, or tri-substituted phenyl, said substituent may be, for example, halogen, alkyl, alkoxy, or halo-substituted alkyl. ##STR2##
(b) U.S. Pat. Nos. 4,254,047, 4,254,048, 4,254,049, 4,170,656, and 4,173,650 disclose a group of compounds that may be represented by the generic structure (IV) wherein X is oxygen, sulfur, methylene, or a direct bond; Ar is phenyl opt. substituted with one or more of the same or different groups selected from halogen, alkyl, alkoxy, trifluoromethyl, and trichloromethyl. ##STR3##
(c) U.S. Pat. No. 4,197,310 discloses thiophenepropionitriles of formula (V) wherein R is hydrogen, lower alkyl, or halogen. ##STR4##
(d) U.S. Pat. Nos. 4,256,759, 4,644,010 and 4,435,407 disclose .beta.-oxo-.beta.-carbamoylpyrrolepropionitriles encompassed by generic formula (VI) where R.sup.1 is H or alkyl; R.sup.2 and R.sup.3 are independently H or alkyl; and R.sup.4 is phenyl or a heterocyclic radical both of which may be opt. substituted with alkyl, alkoxy, hydroxy, halogen, or trifluoromethyl. ##STR5##
(e) German Offenlegungschrift No. 3,217,446 discloses thiocarbamoyl-thenoylacetonitriles of formula (VII) wherein R.sup.1 is H, halogen, alkyl, or alkoxy; R.sup.2 is C.sub.3-6 cycloalkyl, benzyl, furfuryl, or phenyl opt. substituted with halogen alkyl, alkoxy, alkylthio, or trifluoromethyl. ##STR6##
Thus the 2-oxopropanenitrile antiarthritic agents disclosed in the prior art are all keto substituted compounds. Compounds of the present invention do not have a keto group; instead they have a carboxylic acid ester, thioester, or amide substituent. In this manner, compounds of the present invention are distinct over those disclosed in items (a) to (e) above.
A list of references disclosing cyanoacetic acid derivatives is given below; however, the compounds described therein have not been reported as anti-inflammatory or anti-arthritic agents.
(f) British Pat. No. 1,112,210 discloses 2-cyanomalonic acid thioamide derivatives of formula (VIII) wherein R.sup.1 is inter alia alkyl or aralkyl; R.sup.2 is H, alkyl, or aryl; and R.sup.3 is alkyl or aralkyl. ##STR7## These compounds are said to be useful as bactericides, fungicides, and diuretics.
(g) U.S. Pat. No. 3,406,183 discloses 3-N-arylamino-3-mercapto-2-cyano-acrylamides of the formula (IX) wherein R.sup.1 is H and R.sup.2 is alkyl or phenyl; or R.sup.1 and R.sup.2 together represent --(CH.sub.2).sub.4-5 --; and Ar is opt. substituted phenyl. ##STR8## These compounds are alleged to be useful as anthelmintic and antibacterial agents.
(h) Pabst (Arch. Pharm., 1929, 267:325-52) reported the preparation of a series of 2-cyanomalonamic acid esters and amides, for example, (X) and (XI). ##STR9##
(i) U.S. Pat. No. 3,016,295 discloses 2-cyanomalonamic acid ester derivatives having formula (XII) wherein R.sup.1 is alkyl or alkyl--(OCH.sub.2 CH.sub.2 --).sub.1-2 and R.sup.2 is H or alkyl. ##STR10## These compounds are said to be useful in altering growth characteristics of plants.
U.S. Pat. No. 3,909,231 discloses the compound .alpha.-(3,4-dichlorophenyl)carbamoyl cyanoacetic acid ethyl ester as a bactericide and fungicide.